Bacterial Infections in Cirrhosis

Mario U. Mondelli

Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine, University of Pavia, Italy.

Middle East School of Hepatology (MESH), Dubai, November 15, 2013

Key Concepts in Bacterial Infections in Cirrhosis

• Cirrhosis is an independent risk factor for infections.

• Bacterial infections are a leading cause of acute liver failure and are associated with high mortality in end-stage liver disease 1.

• Dysfunction of the immune defensive mechanisms makes patients with cirrhosis prone to the development of sepsis and SBP 2,3.

[1] Bajaj JS, et al. Gut 2012;61:1219–25. [2] Garcia-Tsao G. Gastroenterology 2001;120:726–48. [3] Navasa M, Rodes J. Liver Int 2004;24:277–80.

Bacterial Infections in Cirrhosis

• Epidemiology• Pathogenesis• Clinical manifestations• Diagnosis• Prophylaxis• Treatment

A Multidisciplinary Perspective on the Management of HCC

Study (publication year) Odds ratio (95% CI) % WeightStrauss (1993) 2.96 (1.84–4.75) 16.0Terg (1987) 5.00 (1.23–20.24) 2.2Sharma (1987) 4.16 (1.81–9.57) 5.9Tito (1988) 3.81 (2.14–6.78) 11.5Wang (1991) 5.07 (2.20–11.68) 5.9Caly (1993) 7.29 (2.62–20.22) 4.0Toledo (1993) 6.52 (2.51–16.95) 4.6BAC (1993) 2.40 (0.86–6.70) 4.0Bernard (1995) 5.35 (1.62–17.60) 3.0Wang (2000) 5.33 (1.79–15.86) 3.5Vivas (2001) 23.00 (4.35–121.73) 1.6Borzio (2001) 2.60 (1.35–5.00) 9.2Yoneyama (2002) 2.79 (1.47–5.27) 9.6de Mattos (2002) 3.50 (1.51–8.14) 5.8Plessier (2003) 2.22 (0.40–12.29) 1.5Cholongitas (2006) 10.11 (3.01–33.92) 2.9Fasolato (2007) 2.12 (1.00–4.51) 7.1Piekarska (2008) 5.78 (1.27–26.26) 1.9Overall (95% CI) 3.76 (3.05–4.63)

Arvaniti V, et al. Gastroenterology 2010;139:1246–56

In patients with cirrhosis, infections result in a 4-fold increase mortality 30% of patients die within 1 month after infection A further 30% die by 1 year

Meta-analysis (18 studies) on the rate of deaths in cirrhotic patients with and without infection

0.5 1 3 10

Mortality higher in non-infected Mortality higher in infected

Cirrhotic HCV Patients with Infections Carry a High Risk of Death

Prevalence and Risk Factors of Bacterial Infections in Cirrhotic Patients

• The prevalence of bacterial infections in hospitalized cirrhotics is >30%1.

• Risk higher in CTP C than in CTP A/B or in patients with MELD >15.

Additional risk factors:– Alcohol abuse – History of previous infection – GI bleeding

[1] Fagiuoli S, et al. Dig Liver Dis 2013, in press

Cirrhosis Associated Immune Dysfunction Syndrome : Role of Impaired Immune System

Bonnel AR et al Clin Gastroenterol Hepatol 2011

Cirrhosis Associated Immune Dysfunction Syndrome: Role of Portal Hypertension and Porto-Systemic Shunts

Bonnel AR et al Clin Gastroenterol Hepatol 2011

0

25

50

75

100

SBP No SBP

Small Intestine Bacterial Overgrowth in Cirrhotics and SBP

CS. Chang et al. Hepatology 1998 ; 28 : 1187-1190.

P <0.01Per

cen

t

Factors Contributing to BacterialOvergrowth in the Small Intestine of Cirrhotic Patients

• Reduced gastric acid secretion (role of PPI?)

• Reduced intestinal peristalsis

• Defective mucosal immunity

Wiest R & Garcia Tsao G. Hepatology 2005;41:422-433

Mechanisms of Bacterial Translocation

Markers of Bacterial Translocation

Death of Gram-negative bacteria and release of LPS, bactDNA, lipoproteins

bactDNA+patients

bactDNA-patients

63.4%36.6%

E. coli

E. faecium

K. pneumoniae

S. aureus

57.7%

7.7%

7.7%

26.9%

Prevalence of Bact-DNA in Patients with Cirrhosis and Refractory Ascites

P. Angeli et al . (AASLD 2010)

Bacteria Responsible for Infection in Cirrhotics

• Bacteria of intestinal origin, particularly E. coli are most often involved in community-acquired infections.

• Methicillin-resistant S. aureus (MRSA) is an increasingly frequent MDR pathogen.

• Patients receiving quinolone prophylaxis are at increased risk of resistance.

• Increased resistance to quinolones and 3rd generation cephalosporins in Enterobacteriaceae, including E. coli and Klebsiella species.

Gustot T, et al. Hepatology 2009;50:2022–33. Rimola A, et al. J Hepatol 2000;32:142–53.Merli M, et al. Clin Gastroenterol Hepatol 2010;8:979–85. Tandon P, Garcia-Tsao G. Sem Liver Dis 2008;28:26–42.Fernandez J, et al. Hepatology 2012;55:1551–61..

Clinical Manifestations of Bacterial Infections in Patients with Cirrhosis

• Most common bacterial infections:– SBP (14-25%)– UTI (20%)– Pneumonia (15%) – Bacteraemia (12%)– Cellulitis (variable)– Medical manoeuvres (TIPS, tracheal intubation, oesophageal balloon

tamponade, antiviral treatments)

• SBP is commonly observed in cirrhotic patients who recovered from an episode of SBP and/or with low (<1.5 g/dl) ascites protein concentration 1. – Impaired renal function on admission is associated with increased

mortality 2.

Borzio M, et al. Dig Liver Dis 2001;33:41–8. Fasolato S, et al. Hepatology 2007;45:223–9. Merli M, et al. Clin Gastroenterol Hepatol 2010;8:979–85. Tandon P, Garcia-Tsao G. Sem Liver Dis 2008;28:26–42.Fernandez J, et al. Hepatology 2012;55:1551–61.[1] Guarner C, et al.Gastroenterology 1999;117:414–9. [2] Barahona-Garrido J, et al. J Clin Gastroenterol 2010;44:e218–23.

Outcomes in Clinical Practice: CUPIC Cohort of the French EAP – Week 16 Interim Analysis

*septicemia, septic shock, pneumopathy (2), endocarditis, bleeding from oesophageal varices, ‡pneumopathy.

Hézode C, et al. Hepatology 2012;56(Suppl. 4):217A

When Infection Should Be Suspected ?

• Onset of porto-systemic encephalopathy without obvious causes.

• Deterioration of renal function. • Increase WBC count. • Deterioration of liver function tests.• Fever (differential diagnosis of FUO).

Diagnosis of Bacterial Infection

• Biological fluid cultures are the basic tests for the diagnosis of bacterial infections and should be carried out before initiation of antibiotic therapy.

• Collection, analytical phases (direct and indirect identification,confirmation and susceptibility test) must be performed according to standard operating procedures (SOP).

Diagnostic Work-Up in Cirrhotic Patients with Suspected Infection

• Identification of symptoms and signs of SIRS, severe sepsis or septic shock.

• Assessment of organ function.• Identification of source of infection in body fluids or suspected sites.• Diagnostic paracentesis (PMN count, protein concentration,

Gram stain, bedside cultures) strongly recommended on admission in all patients with ascites [1-3].

• US scan if abdominal symptoms. • Stool culture and C. difficile toxin assay if GI symptoms• If fungal infection is suspected in immunosuppressed patients,

galactomannan in sputum or BAL and cryptococcal serum antigen should be assayed and high-resolution CT should be considered.

[1] Runyon BA, et al. Gastroenterology 1988;95:1351–5. [2] Nguyen-Khac E, et al. Aliment PharmacolTher 2008;28:282–8. [3] Mendler MH, et al. J Hepatol 2010;53:477–83.

CRP

• Historically used,

reliable marker

• Highly sensitive

PCT

• Specificity for sepsis (Gram neg. ++) higher than CRP

• Correlates with the severity of clinical symptoms

Luzzani A et al.. Crit Care Med 2003;31:1737-41

Where Is PCT Expressed ?

THYROID C Cells(calcitonin)

LIVER HYSTIOCYTES(procalcitonin)

LEUKOCYTES (?)(procalcitonin)

A Multidisciplinary Perspective on the Management of HCC

Markers for the Diagnosis of Sepsis

Muller B, et al. Crit Care Med 2000;28:977–83

Procalcitonin1 ng/mL

C-reactive protein100 mg/mL

Lactate 2 mmol/L

Interleukin-6 50 pg/mL

100

80

60

40

20

20 40 60 80

False positive (%)

100

Tru

e po

sitiv

e (

%)

NPV%

PPV%

Procalcitonin 90 94

C-reactive protein

74 75

Interleukin-6 71 74

Lactate 58 61

NPV: negative predictive value; PPV: positive predictive value

Prophylaxis of Bacterial Infections in Cirrhotics

Role of Antibiotic Prophylaxis

• In consideration of the high risk of resistance, the use of prophylactic antibiotics must be rigorously restricted to patients with the highest risk of developing SBP or other bacterial infections.

When Should Antibiotic Prophylaxis Be Instituted ?

• GI bleeding:– Prevalence of infection: 25-65%– Immediate short-term antibiotic prophylaxis is standard of care

for patients with cirrhosis presenting with upper GI bleeding– Choice of antibiotic based on:

• Patient features• Local epidemiology

– I.V. 3rd generation cephalosporin usually preferred

• Secondary prophylaxis of SBP:– Quinolones (norfloxacin) preferred– Recurrence reduced from 68% to 20% (Gram neg 60% to 3%)– Duration undefined– High risk of resistance

• Primary prophylaxis of SBP?

Chavez-Tapia et al, Alim Pharm Ther 2011

ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDINGMETA-ANALYSIS

PREVENTION OF BACTERIAL INFECTION

OVERALL MORTALITY

Chavez-Tapia et al, Alim Pharm Ther 2011

ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDINGMETA-ANALYSIS

MORTALITY DUE TO BACTERIAL INFECTION

Chavez-Tapia et al, Alim Pharm Ther 2011

ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDINGMETA-ANALYSIS

PREVENTION OF

BACTERIAL INFECTION

Chavez-Tapia et al, Alim Pharm Ther 2011

ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDINGMETA-ANALYSIS

ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDINGNORFLOXACINE vs CEFTRIAXONE

Fernandez et al, Gastroenterology 2006

SBP INFECTIONS

ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING

• Available information does not allow to establish the best regimen for antibiotic prophylaxis.

• I.V. Ceftriaxone (1 g/day for 7 d) should be preferred in patients with advanced cirrhosis (ascites, malnutrition, serum bilirubin >3 mg/dl), in hospital settings with high prevalence of quinolone-resistant bacterial infections and in patients on quinolone prophylaxis.

• Oral norfloxacine (400 mg b.i.d. for 7 d) or an alternative oral quinolones can be used in patients with less severe disease.

SBP• SBP is a bacterial infection of ascitic fluid without any

intraabdominal surgically treatable source of infection. • Prevalence of SBP is 1.5-3.5% in outpatients and about

10% in hospitalized patients.• Diagnosis of SBP is based on ascites PMN count 250/L.• PMN counts 250/L excludes SBP (in patients with

haemorragic ascites substract 1 PMN per 250 RBC).• A diagnosis of SBP solely on the basis of clinical symptoms

is not acceptable. • Severe renal failure is common in patients with SBP and is

associated with poor outcome.• Mortality is still about 20%.

A. Rimola, et al. J. Hepatol. 2000 ; 32 : 142-153.

Patients at High Risk of Developing SBP

1. Patients with acute gastrointestinal haemorrhage.

2. Patients with low total protein content in ascitic fluid and no prior history of SBP (primary prophylaxis).

3. Patients with a previous history of SBP (secondary prophylaxis)

Fever 50-75%

Abdominal pain 27-72%

Chills 16-29%

Nausea and vomiting 8-21 %

Diarrhea up to 32%

Ileus up to 30%

Shock up to 21%

Encephalopathy up to 50%

Renal failure up to 34 %

Asymptomatic up to 13 %

Symptoms of SBP

3.5% of pts. with refractory or recurrent ascites may be asymtomatic

TA. Sheer, et al. Dig. Dis. 2005 ; 23 : 39-46 2003 ; 98 : 1844-1848.

• Renal failure 29 25.0

Onset of renal failure 10 8.6

Impairment of pre-existing renal failure 20 17.2

Type 1 HRS 19 16.4

Cirrhotic patients with ascites and SBP (n=116)

Prevalence of Renal Failure Precipitated by SBP

P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84.

n ° %

Sensitivity and Specificity of a Multistix Reagent Strip c/o≥ 2 in Ascitic Fluid in the Diagnosis of SBP

AuthorN° of

patientsSensitivity

(%)Specificity

(%)

Delaunay-Tardy K, 2003 50 60 98

Campillo B, 2006 116 45.7 98

Kim DK, 2005 257 100 99

Butani RC, 2004 75 83 99

Ribero TC, 2007 82 71 99

E. Nguyen-Khac et al. Alim. Pharmacol. Ther. 2008 ; 28 : 282-288.

Patients with Prior SBP

• Recurrence rate at 1 year is 70% 1.

• Probability of survival:– 1 yr 30–50%– 2 yrs 25–30%

[1] Garcia-Tsao G. Gastroenterology 2001;120:726–748.

Secondary SBP Prophylaxis

• Long-term antiobiotic prophylaxis is recommended in all patients with prior SBP.

• Administration of norfloxacin 400 mg/day (or other quinolones) is the first-choice regimen 1.

• Prophylactic therapy should be instituted after the completion of antibiotic therapy for acute SBP, but its duration is unknown.

• The efficacy of prophylaxis with oral quinolones in patients with SBP caused by Gram-pos bacteria or by quinolone-resistant Gram-neg bacteria is questionable

[1] Ginès P, et al. Hepatology 1990;12:716–724.

Fernandez et al, Gastroenterology 2007

PRIMARY PROPHYLAXISNORFLOXACIN 400 mg/day

Bacterial Resistance

• Quinolones: 30%

• Co-Trimoxazole: 30%. 70% of quinolone-resistant Gram - are also resistant to TMX

• No efficacy against Gram + cocci and anaerobes

Primary SBP Prophylaxis

• Cirrhotic patients with low ascitic fluid protein concentration (15 g/L) and/or high serum bilirubin are at risk of developing a first episode of SBP 1,2.

• Clinical trials assessing the beneficial effect of norfloxacin prophylaxis in patients at risk of a first episode of SBP showed reduced incidence of Gram- bacterial infections, with reduced incidence of SBP and a favourable impact on survival and/or occurrence of HRS 3-6.

• In patients with moderate liver disease, ascites protein concentration 15 g/L, and without prior history of SBP, the efficacy of quinolones in preventing SBP or improving survival is not clearly established.

[1] Runyon BA. Gastroenterology 1986;91:1343–6. [2] Garcia-Tsao G. Gastroenterology 2001;120:726–48. [3] Novella M, et al. Hepa-tology 1997;25:532–6. [4] Grange JD, et al. J Hepatol 1998;29:430–6.[5] Fernandez J, et al. Gastroenterology 2007;133:818–24. [6] Terg R, et al. J Hepatol 2008;48:774–9.

PROPHYLAXIS OF BACTERIAL INFECTIONS

Due to the emergence of resistant bacteria with long-term

antibiotic prophylaxis, novel antibiotic regimens or alternative

approaches to prophylaxis should be developed and tailored

according the stratification of the patient risk profile and the

actual local bacterial antibiotic-resistance pattern.

Indicators of Selective Pressure

• Ceftazidime-resistant Enterobacteriaceae• MRSA• VRE• ESBL-producing Enterobacteria• Clostridium difficile

Empirical vs Targeted Therapy for Infection in Cirrhotic Patients

SBP

• SBP is either community or hospital acquired and the commonest bacterial infection in cirrhotics.

• Empirical treatment should be oriented towards SBP and started when ascitic fluid PMN count >250/L and/or with positive cultures which MUST be obtained whenever possible.

• Common pathogens include Enterobacteriaceae, Streptococcus and Staphylococcus spp.

What Are the Best Options for Empirical Treatment of SBP?

• 3rd generation cephalolosporins, such as cefotaxime 2 g bid for 5 days is an effective option.

• P.O. or I.V. quinolones have similar efficacy as cephalosporins; however, they should be avoided in patients receiving NFX prophylaxis and have worst resistance profile.

• Data on quinolone-resistant and ESBL-producer strains of Enterobacteriaceae in SBP are missing in cirrhotic patients.

• Carbapenem or tigecycline may be used with caution in case of documented resistance.

• Combinations of drugs still active against ESBL or class C (Beta lactamase) (AmpC)-producing enterobacteria should be preferred.

Albumin in the Treatment of SBP?

• HRS occurs in approximately 30% of patients with SBP treated with antibiotics alone, and is associated with 20% in-hospital mortality.

• Albumin (1.5 g/kg at diagnosis and 1g/kg on day 3) decreases the frequency of HRS (from 30 to 10%) and reduces mortality (from 29 to 10%) [1].

[1]Sort P, et al. N Engl J Med 1999;341:403–409.

Summary

• Bacterial infections are highly prevalent in cirrhosis and are a major cause of morbidity and mortality.

• Pathogenesis is complex and involves bacterial translocation from the gut and impaired (innate) immunity.

• SBP is the most common and life-threatening bacterial infection.

• Whenever possible treatment should be targeted on the causative microorganism.

• Antibiotic prophylaxis is mandatory in high risk patients but should take into consideration the increasing prevalence of resistant bacterial strains in this setting.

Mortality Caused by Infection in Cirrhosis

• Overall mortality is around 38% with 30.3% of cases occurring at 1 month and 63% at 12 months, with the pooled odds ratio for death of infected vs uninfected of 3.75 (95% CI 2.12–4.23) 1.

• Spontaneous bacterial peritonitis (SBP) represents one of the most common infectious complications in patients with cirrhosis with a median mortality of 43.7% 2.

• Severe renal failure is common in patients with SBP and is associated with poor outcome.

[1] Arvaniti V, et al.Gastroenterology 2010;139:1246–56. [2] Perdomo Coral G, et al. Can J Gastroenterol 2003;17:187–90.